Block copolymers based on poly(ortho esters) containing amine groups

ABSTRACT

Block copolymers based on poly(ortho esters) containing amine groups. These block copolymers have both hydrophilic and hydrophobic blocks. They form micelles in aqueous solution, making them suitable for encapsulation or solubilization of hydrophobic or water-insoluble materials; and they also form bioerodible matrices for the sustained release of active agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of application Ser. No.10/295,766, filed Nov. 14, 2002, which is a continuation-in-part ofapplication Ser. No. 09/991,537, filed Nov. 16, 2001. Each of theseapplications is incorporated into this application by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This application relates to block copolymers based on poly(orthoesters) containing amine groups.

[0004] 2. Description of the Related Art

[0005] Interest in synthetic biodegradable polymers for the systemicdelivery of therapeutic agents began in the early 1970's with the workof Yolles et al., Polymer News 1:9-15 (1970) using poly(lactic acid).Since that time, numerous other polymers have been prepared andinvestigated as bioerodible matrices for the controlled release oftherapeutic agents.

[0006] U.S. Pat. Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344 and4,180,646 disclose biodegradable or bioerodible poly(ortho esters).These polymers are formed by a reaction between an orthoester (ororthocarbonate) such as 2,2-diethoxytetrahydrofuran and a diol such as1,4-cyclohexanedimethanol. The reaction requires elevated temperatureand reduced pressure and a relatively long reaction time. Drugs or otheractive agents are retained in the polymer matrix to be released as thepolymer biodegrades due to hydrolysis of the labile linkages.

[0007] U.S. Pat. No. 4,304,767 discloses polymers prepared by reacting apolyol with a polyfunctional ketene acetal. These polymers represent asignificant improvement over those of U.S. Pat. Nos. 4,079,038,4,093,709, 4,131,648, 4,138,344 and 4,180,646, since synthesis proceedsreadily at room temperature and atmospheric pressure, and the resultingpolymers have superior properties.

[0008] Further polymers are disclosed in U.S. Pat. No. 4,957,998. Thesepolymers contain acetal, carboxy-acetal and carboxy-orthoester linkages,and are prepared by a two-step process beginning with the reactionbetween a polyfunctional ketene acetal and a compound containing a vinylether, followed by reaction with a polyol or polyacid.

[0009] Still further polymers of a similar type are disclosed in U.S.Pat. No. 4,946,931. The polymers are formed by a reaction between acompound containing a multiplicity of carboxylate functions and apolyfunctional ketene acetal. The resulting polymers have very rapiderosion times.

[0010] Despite the ease with which the orthoester linkage hydrolyses,poly(ortho esters) known in the prior art are extremely stable materialswhen placed in an aqueous buffer, or when residing in the body. Thisstability is attributable to the extreme hydrophobicity of thepoly(ortho esters) which severely limits the amount of water that canpenetrate the polymer. To achieve useful erosion rates, therefore,acidic excipients must be physically incorporated into the polymer.While this allows control over erosion rates, the physicallyincorporated acidic excipient can diffuse from the polymer matrix atvarying rates, leaving a matrix that is completely depleted of excipientwhile the polymer still has a very long lifetime remaining.

[0011] U.S. Pat. Nos. 4,764,364 and 4,855,132 describe bioerodiblepolymers, in particular poly(ortho esters) containing an aminefunctionality. The polymers are said to erode more rapidly at lower pHthan at higher pH in an acidic aqueous environment.

[0012] Micellar System for Tumor Targeting

[0013] One of the major problems in treating cancer is the difficulty ofachieving a sufficient concentration of an anticancer agent in thetumor. This is due to the toxicity, sometimes extreme, of such agentswhich severely limits the amounts that can be used. However, a majordiscovery in cancer chemotherapy has been the so-called EPR (enhancedpermeation and retention) effect. The EPR effect is based on theobservation that tumor vasculature, being newly formed vasculature, hasan incompletely formed epithelium and is much more permeable thanestablished older vasculature which is essentially impermeable to largemolecules. Further, lymphatic drainage in tumors is very poor thusfacilitating retention of anticancer agents delivered to the tumor.

[0014] The EPR effect can be used in cancer targeting by using deliverysystems containing anticancer drugs that are too large to permeatenormal vasculature, but which are small enough to permeate tumorvasculature, and two approaches have been developed. In one approach, awater-soluble polymer is used that contains an anticancer drugchemically bound to the polymer via a hydrolytically labile linkage.Such drug-polymer constructs are injected intravenously and accumulatein the tumors, where they are internalized by the cells via endocytosisand released in the lysosomal compartment of the cell via enzymaticcleavage of the labile bond attaching the drug to the polymer. Twodisadvantages of this approach are that, first, nondegradable,water-soluble polymers have been used, and this requires a tediousfractionation of the polymer to assure that the molecular weight of thepolymer is below the renal excretion threshold, and, second, the drugmust be chemically attached to the polymer, which in effect creates anew drug entity with consequent regulatory hurdles that must beovercome. The use of polymer conjugates in cancer diagnosis andtreatment is discussed in Duncan et al., “The role of polymer conjugatesin the diagnosis and treatment of cancer”, S. T. P. Pharma Sciences,6(4), 237-263 (1996), and an example of an alginate-bioactive agentconjugate is given in U.S. Pat. No. 5,622,718.

[0015] An alternate approach has been described. In this approach, an ABor ABA block copolymer is prepared where the B-block is hydrophobic andthe A-block is hydrophilic. When such a material is placed in water, itwill self-assemble into micelles with a hydrophobic core and ahydrophilic shell surrounding the core. Such micelles have a diameter ofabout 100 nm, which is large enough that when they are injectedintravenously, the micelles can not leave the normal vasculature, butthey are small enough to leave the vasculature within tumors. Further, a100 nm diameter is too small to be recognized by the reticuloendothelialsystem, thus enhancing micelle lifetime within the blood stream.Additionally, when the hydrophilic block is poly(ethylene glycol),further enhancement of circulation time is noted, as has been observedwith “stealth” liposomes. The use of block copolymer micelles isreviewed in Kwon et al., “Block copolymer micelles as long-circulatingdrug delivery vehicles”, Adv. Drug Delivery Rev., 16, 295-309 (1995).

[0016] U.S. Pat. Nos. 5,412,072; 5,449,513; 5,510,103; and 5,693,751describe block copolymers useful as micellar delivery systems where thehydrophilic block is polyethylene glycol and the hydrophobic blocks arevarious derivatives of poly(aspartic acid), poly(glutamic acid) andpolylysine. U.S. Pat. Nos. 5,412,072 and 5,693,751 describe an approachwhere drugs have been chemically attached to the hydrophobic segment;while U.S. Pat. Nos. 5,449,513 and 5,510,103 describe an approach wherehydrophobic drugs have been physically entrapped within the hydrophobicportion of the micelle. This latter approach is clearly preferablebecause no chemical modification of the drug is necessary.

[0017] Bioerodible Block Copolymer Matrix for Controlled Drug Delivery

[0018] In AB, ABA, or BAB block copolymers comprising a hydrophilic Ablock and a hydrophobic B block, the A and B blocks are incompatible andon a microscopic scale will phase-separate. This phase separationimparts unique and useful thermal properties to the material.

[0019] There is considerable prior art in the development of blockcopolymers comprised of poly(ethylene glycol) and bioerodiblehydrophobic segments such as poly(L-lactic acid),poly(L-lactic-co-glycolic acid) copolymers and poly(e-caprolactone), anddiscussion of their use as drug delivery agents. For example, seeWolthuis et al., “Synthesis and characterization of poly(ethyleneglycol) poly-L-lactide block copolymers”, Third Eur. Symp. ControlledDrug Delivery, 271-276 (1994), Youxin et al., “Synthesis and propertiesof biodegradable ABA triblock copolymers . . . ”, J. Controlled Release,27, 247-257 (1993), and U.S. Pat. No. 5,133,739.

[0020] Poly(ortho esters) are known as potential vehicles for sustainedrelease drug delivery. See, for example, Heller, “Poly(Ortho Esters)”,Adv. Polymer Sci., 107, 41-92 (1993), and references cited therein, andU.S. Pat. Nos. 4,304,767, 4,946,931, 4,957,998, and 5,968,543.

[0021] U.S. Pat. No. 5,939,453 describes block copolymers prepared frompolyethylene glycols and certain poly(ortho esters).

[0022] The documents listed in this section and elsewhere throughoutthis application are incorporated into this application by reference.

SUMMARY OF THE INVENTION

[0023] In a first aspect, this invention is block copolymers of formulaX, formula Y, and formula Z:

R^(A)-[OCH₂CH₂]_(f)-[POE]_(g)-H  (X),

R^(A)-[OCH₂CH₂]_(f)-[POE]_(g)-[OCH₂CH₂]_(h)—OR^(B)  (Y),

H-A-[POE]_(g)-[OCH₂CH₂]_(h)-[POE]_(j)-H  (Z),

[0024] where:

[0025] R^(A) is C₁-C₄ alkyl;

[0026] R^(B) is C₁-C₄ alkyl;

[0027] f and h are independently an integer from 2 to 1000;

[0028] g and j are independently an integer from 2 to 200;

[0029] POE is a poly(ortho ester) unit of formula IA or formula IIA:

[0030] where

[0031] R* is a C₁-C₄ alkyl;

[0032] R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a isan integer of 1 to 10, and b and c are independently integers of 1 to 5;and

[0033] each A is independently selected from R¹, R², R³, and R⁴, where

[0034] R¹ is:

[0035] where:

[0036] p is an integer of 1 to 20;

[0037] R⁵ is hydrogen or C₁-C₄ alkyl; and

[0038] R⁶ is:

[0039] where:

[0040] s is an integer of 0 to 30;

[0041] t is an integer of 2 to 200; and

[0042] R⁷ is hydrogen or C₁-C₄ alkyl;

[0043] R² is:

[0044] R³ is:

[0045] where:

[0046] x is an integer of 0 to 30;

[0047] y is an integer of 2 to 200;

[0048] R⁸ is hydrogen or C₁-C₄ alkyl;

[0049] R⁹ and R¹⁰ are independently C₁-C₁₂ alkylene;

[0050] R¹¹ is hydrogen or C₁-C₆ alkyl and R¹² is C₁-C₆ alkyl; or R¹¹ andR¹² together are C₃-C₁₀ alkylene; and R⁴ is the residue of a diolcontaining at least one amine functionality incorporated therein; inwhich at least 0.1 mol % of the A units are R¹, and at least 0.1 mol %of the A units are R⁴.

[0051] In a second aspect, this invention is a micellar pharmaceuticalcomposition for the delivery of a hydrophobic or water-insoluble activeagent, comprising the active agent physically entrapped within but notcovalently bonded to a drug carrier comprising a block copolymer offormula X, formula Y, or formula Z, or a mixture thereof.

[0052] In a third aspect, this invention is a composition for thesustained release of an active agent, comprising the active agentdispersed in a matrix comprising a block copolymer of formula X, formulaY, or formula Z, or a mixture thereof.

[0053] In an fourth aspect, this invention is a process for thepreparation of a block copolymer of formula X, formula Y, or formula Z,as described in the “Detailed description of the invention”.

DETAILED DESCRIPTION OF THE INVENTION

[0054] It has now been discovered that poly(ortho esters) useful asorthopedic implants or vehicles for the sequestration and sustaineddelivery of drugs, cosmetic agents and other beneficial agents can beprepared in such a manner that the rate and degree to which they arehydrolyzed by contact with bodily fluids at normal body temperature andpH can be controlled without addition of exogenous acid. This discoveryresides in the incorporation of esters of short-chain α-hydroxy acidssuch as esters of glycolic acid, lactic acid or glycolic-co-lactic acidcopolymer into the poly(ortho ester) chain and variation of the amountof these esters relative to the poly(ortho ester) as a whole.

[0055] In the presence of water, these esters, when incorporated intothe poly(ortho ester) chain, are readily hydrolyzed at a bodytemperature of 37° C. and a physiological pH, in particular at a pH of7.4, to produce the corresponding α-hydroxy acids. The α-hydroxy acidsthen act as an acidic excipient to control the hydrolysis rate of thepoly(ortho ester) portion of the block copolymer. When the blockcopolymer is used as a vehicle or matrix entrapping an active agent, thehydrolysis of the poly(ortho ester) causes release of the active agent.

[0056] The use in these poly(ortho esters) of diols containing aminefunctionalities causes the poly(ortho esters) to become morepH-sensitive than poly(ortho esters) not containing such diols, and thusto hydrolyze yet more readily at lower pH than at higher pH. This isparticularly so in an acidic aqueous environment, such as is foundwithin animal cells, and enables the poly(ortho esters) to be relativelystable within the extracellular environment within an animal, such aswithin the blood, but to hydrolyze rapidly within the intracellularenvironment. This makes these poly(ortho esters) particularly suitablefor delivery of active agents within the cell.

[0057] Definitions

[0058] Unless defined otherwise in this specification, all technical andscientific terms are used herein according to their conventionaldefinitions as they are commonly used and understood by those ofordinary skill in the art of synthetic and pharmaceutical chemistry.

[0059] “Active agent” includes any compound or mixture of compoundswhich produces a beneficial or useful result. Active agents aredistinguishable from such components as vehicles, carriers, diluents,lubricants, binders and other formulating aids, and encapsulating orotherwise protective components. Examples of active agents arepharmaceutical, agricultural or cosmetic agents. Suitable pharmaceuticalagents include locally or systemically acting pharmaceutically activeagents which may be administered to a subject by topical orintralesional application (including, for example, applying to abradedskin, lacerations, puncture wounds, etc., as well as into surgicalincisions) or by injection, such as subcutaneous, intradermal,intramuscular, intraocular, or intra-articular injection. Examples ofthese agents include, but not limited to, anti-infectives (includingantibiotics, antivirals, fungicides, scabicides or pediculicides),antiseptics (e.g., benzalkonium chloride, benzethonium chloride,chlorhexidine gluconate, mafenide acetate, methylbenzethonium chloride,nitrofurazone, nitromersol and the like), steroids (e.g., estrogens,progestins, androgens, adrenocorticoids, and the like), therapeuticpolypeptides (e.g. insulin, erythropoietin, morphogenic proteins such asbone morphogenic protein, and the like), analgesics andanti-inflanimatory agents (e.g., aspirin, ibuprofen, naproxen,ketorolac, COX-1 inhibitors, COX-2 inhibitors, and the like), cancerchemotherapeutic agents (e.g., mechlorethamine, cyclophosphamide,fluorouracil, thioguanine, carmustine, lomustine, melphalan,chlorambucil, streptozocin, methotrexate, vincristine, bleomycin,vinblastine, vindesine, dactinomycin, daunorubicin, doxorubicin,tamoxifen, and the like), narcotics (e.g., morphine, meperidine,codeine, and the like), local anesthetics (e.g., the amide- oranilide-type local anesthetics such as bupivacaine, dibucaine,mepivacaine, procaine, lidocaine, tetracaine, and the like),antiangiogenic agents (e.g., combrestatin, contortrostatin, anti-VEGF,and the like), polysaccharides, vaccines, antigens, DNA and otherpolynucleotides, antisense oligonucleotides, and the like. The presentinvention may also be applied to other locally acting active agents,such as astringents, antiperspirants, irritants, rubefacients,vesicants, sclerosing agents, caustics, escharotics, keratolytic agents,sunscreens and a variety of dermatologics including hypopigmenting andantipruritic agents. The term “active agents” further includes biocidessuch as fungicides, pesticides, and herbicides, plant growth promotersor inhibitors, preservatives, disinfectants, air purifiers andnutrients.

[0060] “Alkyl” denotes a linear saturated hydrocarbyl having from one tothe number of carbon atoms designated, or a branched or cyclic saturatedhydrocarbyl having from three to the number of carbon atoms designated(e.g., C₁-C₄ alkyl). Examples of alkyl include methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, t-butyl, cyclopropylmethyl, and thelike.

[0061] “Alkylene” denotes a branched or unbranched saturated divalentradical having from one to the number of carbon atoms designated (e.g.,C₁-C₁₂ alkylene). Examples of alkylene include methylene (—CH₂—),ethylene (—CH₂CH₂—), isopentylene (—CH₂—CH(CH₃)—CH₂—CH₂—), n-octylene(—(CH₂)₈—) and the like.

[0062] “Bioerodible” and “bioerodibility” refer to the degradation,disassembly or digestion of the poly(ortho ester) by action of abiological environment, including the action of living organisms andmost notably at physiological pH and temperature. A principal mechanismfor bioerosion of the poly(ortho esters) of the present invention ishydrolysis of linkages between and within the units of the poly(orthoester).

[0063] “Comprising” is an inclusive term interpreted to mean containing,embracing, covering or including the elements listed following the term,but not excluding other unrecited elements.

[0064] “Controlled release”, “sustained release”, and similar terms areused to denote a mode of active agent delivery that occurs when theactive agent is released from the delivery vehicle at an ascertainableand controllable rate over a period of time, rather than dispersedimmediately upon application or injection. Controlled or sustainedrelease may extend for hours, days or months, and may vary as a functionof numerous factors. For the pharmaceutical composition of the presentinvention, the rate of release will depend on the type of the excipientselected and the concentration of the excipient in the composition.Another determinant of the rate of release is the rate of hydrolysis ofthe linkages between and within the units of the poly(ortho ester). Therate of hydrolysis in turn may be controlled by the composition of thepoly(ortho ester) and the number of hydrolysable bonds in the poly(orthoester). Other factors determining the rate of release of an active agentfrom the present pharmaceutical composition include particle size,acidity of the medium (either internal or external to the matrix) andphysical and chemical properties of the active agent in the matrix.

[0065] “Matrix” denotes the physical structure of the block copolymerwhich essentially retains the active agent in a manner preventingrelease of the agent until the block copolymer erodes or decomposes.

[0066] “PEG” means polyethylene glycol, H—[OCH₂CH₂]_(f)—OH, with anumerical suffix indicating the nominal number average molecular weight,Mn. Unless the context requires otherwise, “PEG” also includespolyethylene glycol mono(C₁-C₄ alkyl) ethers, R—[OCH₂CH₂]_(f)—OH, whereR is C₁-C₄ alkyl, sometimes referred to as “RPEG”.

[0067] “POE” means a poly(ortho ester) or a poly(ortho ester) unit.

[0068] “Sequestration” is the confinement or retention of an activeagent within the internal spaces of a block coplymer matrix.Sequestration of an active agent within the matrix may limit the toxiceffect of the agent, prolong the time of action of the agent in acontrolled manner, permit the release of the agent in a preciselydefined location in an organism, or protect unstable agents against theaction of the environment.

[0069] A “therapeutically effective amount” means the amount that, whenadministered to an animal for treating a disease, is sufficient toeffect treatment for that disease.

[0070] “Treating” or “treatment” of a disease includes preventing thedisease from occurring in an animal that may be predisposed to thedisease but does not yet experience or exhibit symptoms of the disease(prophylactic treatment), inhibiting the disease (slowing or arrestingits development), providing relief from the symptoms or side-effects ofthe disease (including palliative treatment), and relieving the disease(causing regression of the disease). For the purposes of this invention,a “disease” includes pain.

[0071] A “unit” denotes an individual segment of a poly(ortho ester)chain, which consists of the residue of a diketene acetal molecule andthe residue of a polyol.

[0072] An “α-hydroxy acid containing” unit denotes a unit where A is R¹,i.e. in which the polyol is prepared from an α-hydroxy acid or cyclicdiester thereof and a diol of the formula HO—R⁶—OH. The fraction of thepoly(ortho ester) that is α-hydroxy acid containing units affects therate of hydrolysis (or bioerodibility) of the poly(ortho ester) portionof the block copolymer, and in turn, the release rate of the activeagent.

[0073] An “amine containing” unit denotes a unit where A is R⁴, i.e. inwhich the diol contains an amine functionality. The fraction of thepoly(ortho ester) that is amine containing units affects thepH-sensitivity of the rate of hydrolysis (or bioerodibility) of thepoly(ortho ester) portion of the block copolymer, and in turn, therelease rate of the active agent.

[0074] “Hard” and “soft” units denote individual units of the poly(orthoester), the contents of which relative to the poly(ortho ester) as awhole determine the mechano-physical state of the poly(ortho ester)portion of the block copolymer. “Hard” units are units where A is R² and“soft” units are units where A is R³.

[0075] “Vehicle” and “carrier” denote an ingredient that is included ina composition such as a pharmaceutical or cosmetic preparation forreasons other than a therapeutic or other biological effect. Functionsserved by vehicles and carriers include transporting an active agent toa site of interest, controlling the rate of access to, or release of,the active agent by sequestration or other means, and facilitating theapplication of the agent to the region where its activity is needed.Examples of vehicles and carriers include solids such as microparticles,microspheres, rods, and wafers; and semisolids that are dispensable bysyringe or the like, or by spreading with a tool such as a spatula.

[0076] Ranges given, such as temperatures, times, sizes, and the like,should be considered approximate, unless specifically stated.

[0077] The block copolymers

[0078] The block copolymers are of formula X, formula Y, and formula Z:

R^(A)-[OCH₂CH₂]_(f)-[POE]H  (X),

R^(A)-[OCH₂CH₂]_(f)-[POE]_(g)-[OCH₂CH₂]_(h)—OR^(B)  (Y),

H-A-[POE]_(g)-[OCH₂CH₂]_(h)-[POE]_(j)-H  (Z),

[0079] where:

[0080] R^(A) is C₁-C₄ alkyl;

[0081] R^(B) is C₁-C₄ alkyl;

[0082] f and h are independently an integer from 2 to 1000;

[0083] g and j are independently an integer from 2 to 200;

[0084] POE is a poly(ortho ester) unit of formula IA or formula IIA:

[0085] where

[0086] R* is a C₁-C₄ alkyl;

[0087] R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a isan integer of 1 to 10, and b and c are independently integers of 1 to 5;and

[0088] each A is independently selected from R¹, R², R³, and R⁴, where

[0089] R¹ is:

[0090] where:

[0091] p is an integer of 1 to 20;

[0092] R⁵ is hydrogen or C₁-C₄ alkyl; and

[0093] R⁶ is:

[0094] where:

[0095] s is an integer of 0 to 30;

[0096] t is an integer of 2 to 200; and

[0097] R⁷ is hydrogen or C₁-C₄ alkyl;

[0098] R² is:

[0099] R³ is:

[0100] where:

[0101] x is an integer of 0 to 30;

[0102] y is an integer of 2 to 200;

[0103] R⁸ is hydrogen or C₁-C₄ alkyl;

[0104] R⁹ and R¹⁰ are independently C₁-C₁₂ alkylene;

[0105] R¹¹ is hydrogen or C₁-C₆ alkyl and R¹² is C₁-C₆ alkyl; or R¹¹ andR¹² together are C₃-C₁₀ alkylene; and R⁴ is the residue of a diolcontaining at least one amine functionality incorporated therein; inwhich at least 0.1 mol % of the A units are R¹, and at least 0.1 mol %of the A units are R⁴.

[0106] Because of the polymeric character of these molecules, the numberof repeating units within the blocks, f, g, h, and j necessarilyrepresent averages of distributions rather than exact numbers; and inparticular, when f and h or g and j are described as being the same,this indicates that the average values of f and h, or of g and j, shouldbe approximately the same. Similarly, the lengths of other polymericchains, such as the poly(ethylene glycol) of R⁶; of the long chain diolof R⁶; and of the poly(α-hydroxy acid) group within R¹ necessarilyrepresent averages of distributions rather than exact numbers.

[0107] The copolymers are AB (formula X), ABA (formula Y), and BAB(formula Z) block copolymers in which the A blocks are hydrophilicpoly(ethylene glycol) and the B blocks are hydrophobic poly(orthoester). Within these, the poly(ortho ester) blocks are composed ofalternating residues of a diketene acetal and a diol.

[0108] The properties of the copolymers, including both themechanophysical properties and the bioerodibility, are determined by thetype of the copolymer, whether AB diblock, ABA triblock, or BABtriblock, the length of the PEG and POE blocks, and the diol(s) used inthe POE blocks (in particular, the proportion of diol of the generalformula HO—R¹—OH used in the POE blocks).

[0109] With respect to the individual “α-hydroxy acid containing” unit,p is preferably 1 to 6, more preferably 1 to 4, most preferably 1 or 2,especially 1; R⁵ is preferably hydrogen or methyl, more preferablyhydrogen; and in the above definitions of R⁶, s is preferably 2 to 12,more preferably 2 to 6 and most preferably 2; R⁷ is preferably hydrogen,and t is preferably 4 to 12, more preferably 4 to 6 and most preferably6.

[0110] With respect to the individual “hard” unit, R² is preferablycyclohexanedimethanol.

[0111] With respect to the individual “soft” unit, in the definitions ofR³, x is preferably 2 to 12, more preferably 2 to 6 and most preferably2; R⁸ is preferably hydrogen, and y is preferably 4 to 12, for example10; otherwise, R⁹ and R¹⁰ are preferably identical, more preferably anunbranched C₄-C₁₂ alkylene, and especially an unbranched C₆-C₁₂alkylene, R¹ is preferably hydrogen, and R¹² is preferably methyl.

[0112] With respect to the individual “amine containing” unit, diols ofthe formula HO—R⁴—OH include aliphatic diols of 2 to 20 carbon atoms,preferably 2 to 10 carbon atoms, interrupted by one or two amine groups,and di(hydroxy)- or bis(hydroxyalkyl)-cyclic amines, having from 4 to20, preferably 4 to 10, carbon or nitrogen atoms between the hydroxygroups; and the amine groups are secondary or, preferably, tertiary,amine groups.

[0113] Preferred polymers are those in which one or more of thefollowing are true:

[0114] (1) f and h are independently an integer from 10 to 500,especially from 50 to 250, for example 100, for micellar delivery; and fand h are independently an integer from 50 to 1000, especially from 100to 1000, for example from 250 to 1000, for bioerodible matrices; and fand h are preferably the same if both are present;

[0115] (2) g and j are independently an integer from 5 to 100,especially 10 to 50, for example 15, for micellar delivery; and g and jare independently an integer from 10 to 200, especially from 20 to 200,for example from 50 to 200, for bioerodible matrices; and g and j arepreferably the same if both are present;

[0116] (3) R* is C₂-C₄ alkyl, especially ethyl;

[0117] (4) R^(A) and R^(B) are methyl; and

[0118] (5) the proportion of POE units where A is R¹ is from 0.1 to 10%,in addition to the preferences given above with respect to the variousPOE units.

[0119] While a block copolymer having any one of these preferenceslisted above is preferred over a block copolymer not having thatpreference, the block copolymers will be more preferred the greater thenumber of preferences met.

[0120] The bioerodibility of a block copolymer of this invention isdetermined by two factors: first, the extent to which the copolymer willdissolve/become suspended intact in an aqueous medium, the solubility ofthe copolymer; and second, the extent to which the copolymer, or, to bemore precise, the POE block(s), will degrade in the environment to whichit is exposed. The speed of degradation of the POE block(s) of thecopolymer in an aqueous environment is determined by the hydrophilicityof the copolymer and by the proportion of α-hydroxy acid ester groups,if present, in the block(s), with greater bioerodibility being achievedby inclusion of a greater proportion of diols of the formula HO—R¹—OH inthe diol mixture used to form the POE block(s), and greaterpH-sensitivity of the rate of bioerodibility (making the material morerapidly bioerodible at low pH) being achieved being achieved byinclusion of a greater proportion of diols of the formula HO—R⁴—OH inthe diol mixture used to form the POE block(s).

[0121] Block copolymers having a higher mole percentage of the“α-hydroxy acid containing” units will have a higher rate ofbioerodibility. Preferred block copolymers are those in which the molepercentage of the “α-hydroxy acid containing” units is in the range ofabout 0.1 to about 99 mole percent, such as about 0.5 to about 50 molepercent, more preferably from about 1 to about 30 mole percent, forexample from about 5 to about 30 mole percent, especially from about 10to about 30 mole percent.

[0122] Block copolymers having a higher mole percentage of the “aminecontaining” units will have a rate of bioerodibility that is morepH-sensitive than non-“amine containing” poly(ortho esters), andincreases at lower pH. Preferred block copolymers are those in which themole percentage of the “amine containing” units is in the range of about0.1 to about 99.9 mole percent, more preferably from about 1 to about 80mole percent, for example from about 5 to about 50 mole percent,especially from about 10 to about 30 mole percent.

[0123] The invention includes block copolymers which contain all fourtypes of units as well as block copolymers containing units from onlythe “α-hydroxy acid containing” units and “amide containing” units, or amixture of these units with only one of the “hard” units or “soft”units. It also includes block copolymers prepared from a mixture ofunits which contains two or more diols of the same type.

[0124] Preparation of the Block Copolymers

[0125] The diblock copolymers of formula X are prepared in a two-stepsynthesis.

[0126] In the first step, a PEG lower alkyl ether of the formulaR^(A)—[OCH₂CH₂]_(f)—OH, where R^(A) is C₁-C₄ alkyl (an RPEG), is reactedwith an excess of a di(ketene acetal) of formula III or formula IV:

[0127] to form an intermediate of formula VII or formula VIII:

[0128] Polyethylene glycols, and polyethylene glycol lower alkyl ethersof various chain lengths (molecular weights) are available from a numberof sources, including Aldrich Chemical Company, Inc., Milwaukee, Wis.,and Shearwater Polymers, Huntsville, Ala.

[0129] The preparation of the di(ketene acetals) of the types of formulaIII and formula IV is disclosed in U.S. Pat. Nos. 4,304,767, 4,532,335,and 5,968,543; and will be known to a person of ordinary skill in theart. A typical method is the condensation of a bis(diol) of formula V(i.e. pentaerythritol) or formula VI:

[0130] with two equivalents of a 2-halocarboxaldehyde dialkyl acetal,such as 2-bromoacetaldehyde diethyl acetal, followed bydehydrohalogenation to give the di(ketene acetal). The condensation of aglycol with diethylbromoacetals is described in Roberts et al., J. Am.Chem. Soc., 80, 1247-1254 (1958), and dehydrohalogenation is describedin Beyerstedt et al., J. Am. Chem. Soc., 58, 529-553 (1936).

[0131] The di(ketene acetals) may also be prepared by the isomerizationof di(vinyl acetals). Thus, for example,3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU) may beprepared by the isomerization of3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane, using n-butyllithium inethylenediamine or by photoisomerization. The isomerization of thedouble bond is described in Corey et al., J. Org. Chem., 38, 3224(1973). The di(vinyl acetals) may be prepared by the condensation of thebis(diol) of formula V or formula VI with two equivalents of a vinylicaldehyde, such as acrolein or crotonaldehyde, or their dialkyl acetals,such as acrolein dimethyl acetal, and such condensation reactions arewell known.

[0132] The bis(diol) of formula VI where R is a bond is erythritol. Thebis(diol) of formula VI where R is —(CH₂)_(a)— may be prepared by theoxidation of an α,ω-diene, such as 1,3-butadiene or 1,5-hexadiene, withan oxidizing reagent such as osmium tetroxide/hydrogen peroxide, or byother methods known in the art, to give the bis(diol). The bis(diol) offormula VI where R is —(CH₂)_(b)—O—(CH₂)_(c)— may be prepared by thereaction of an ω-hydroxy-α-olefin, such as allyl alcohol, with anω-haloalkyloxirane, such as epichlorohydrin, to form an ω-epoxy-α-olefinwith the backbone interrupted by an oxygen atom, such as2-allyloxymethyloxirane, which is then oxidized with an oxidizingreagent such as osmium tetroxide/hydrogen peroxide, or by other methodsknown in the art, to give the bis(diol).

[0133] In the second step, a diol of the formula HO—R¹—OH and a diol ofthe formula HO—R⁴—OH, and optionally a diol of the formulae HO—R²—OHand/or HO—R³—OH, or a mixture thereof, is reacted with the solution ofthe first step (containing the intermediate of formula VII or VIII andthe excess di(ketene acetal)) to extend the POE block, thereby formingthe diblock copolymer of formula X.

[0134] The preparation of diols of the formula HO—R¹—OH is generallydisclosed in U.S. Pat. No. 5,968,543, by reacting a cyclic ester of anα-hydroxy acid with a diol of the formula HO—R⁶—OH. Diols of the formulaHO—R²—OH are generally commercially available. Diols of the formulaHO—R³—OH may be commercially available or their preparation is generallydisclosed in Heller et al., J. Polymer Sci., Polymer Letters Ed.18:293-297 (1980), by reacting an appropriate divinyl ether with anexcess of an appropriate diol.

[0135] Diols of the formula HO—R⁴—OH are diols containing at least onesecondary or, preferably, tertiary amine. They include diols where R⁴ isan amine such as R′NR″R′″ or R′N═R′″ where each of R′ and R′″ isindependently an aliphatic, aromatic, or aromatic/aliphatic straight orbranched chain hydrocarbyl to which is bonded one of the hydroxy groupsof the diol, and optionally where R′ and R′″ are bonded so that theamine is a cyclic amine, especially a straight or branched chain alkylof 2 to 10 carbon atoms, and more especially 2 to 5 carbon atoms, and R″is hydrogen, C₁₋₆ alkyl, C₆₋₁₀ aryl, or aralkyl, especially alkyl, andmore especially methyl. Other diols include those where two such aminegroups are present, including in the same cyclic amine. Thusrepresentative cyclic amine-based diols of the formula HO—R⁴—OH includedi(hydroxy)- or bis(hydroxyalkyl)-substituted cyclic amines such assubstituted pyridine, piperidine, pyridazine, pyrimidine, pyrazine,piperazine, and the like. Some representative diols of the formulaHO—R⁴—OH include N,N-bis(2-hydroxyethyl)amine,N,N-bis(2-hydroxyethyl)aniline, N-methyl-N,N-bis(2-hydroxyethyl)amine,N-butyl-N,N-bis(2-hydroxyethyl)amine,N-propyl-N,N-bis(2-hydroxyethyl)amine,N-2-propyl-N,N-bis(2-hydroxyethyl) amine,N-cyclohexyl-N,N-bis(2-hydroxyethyl)amine, N-benzyl-N,N-bis(2-hydroxyethyl)amine, 3-dimethylamino-1,2-propanediol,3-(tert-butylamino)-1,2-propanediol, 1,4-bis (2-hydroxyethyl)piperidine,1,4-bis(2-hydroxyethyl)piperazine, 1,4-bis (hydroxymethyl)piperazine,7-(2,3-dihydroxypropyl)theophylline, 3,6-dihydroxypyridazine,2,3-dihydroxypyridine, 2,4-dihydroxy-pyridine, 2,6-dihydroxypyridine,4,6-dihydroxypyrimidine, N-ethyl-N,N-bis(2-hydroxyethyl)amine, and thelike. Such diols include those containing both secondary and tertiaryamines, though tertiary amines are preferred. Amine-containing polyolsinclude N-3-hydroxypropyl-N,N-bis(2-hydroxyethyl)amine, 1,3-bis[tris(hydroxymethyl)methylamino]propane,2,2-bis(hydroxymethyl)-2,2′,2″-nitrotriethanol,tris(2-hydroxyethyl)amine, tris(3-hydroxypropyl)amine, and the like.These diols are known to the art in reported syntheses and many arecommercially available.

[0136] Since the di(ketene acetal) and the diol react in a 1:1 ratio toform the POE block of the diblock copolymer, the quantities of the RPEG,the diketene acetal, and the diol are chosen so that the molar amount ofdi(ketene acetal) is equal to the sum of the molar amounts of the RPEGand the diol.

[0137] The value of f in the PEG block, i.e. the length of the PEGblock, is determined by the RPEG chosen. The value of g in the POEblock, i.e. the length of the POE block, is determined by the molarquantity of diol relative to the molar quantity of RPEG: the greater themolar quantity of diol (assuming that the di(ketene acetal) is presentin at least an equimolar quantity), the longer is the POE block.

[0138] The triblock copolymers of formula Y are also formed in atwo-step synthesis.

[0139] In the first step, an excess of the di(ketene acetal) of formulaIII or formula IV is reacted with a diol of the formula HO—R¹—OH and adiol of the formula HO—R⁴—OH, and optionally a diol of the formulaHO—R²—OH and/or HO—R³—OH, or a mixture thereof, to form a POE blockwhich is terminated at each end with a di(ketene acetal) unit, giving anintermediate of formula IX or formula X:

[0140] where r is g-2.

[0141] In the second step, the intermediate of formula IX or formula Xis reacted with two equivalents of PEG or an RPEG to form the triblockcopolymer of formula Y.

[0142] Since the di(ketene acetal) and the diol react in essentially a1:1 ratio to form the POE block of the triblock copolymer, but di(keteneacetal) termination of the POE block is desired, the quantities of thedi(ketene acetal) and the diol are chosen so that the molar amount ofdi(ketene acetal) is slightly greater than the molar amount of the diol.The molar ratio of PEG/RPEG to POE block should be approximately 2:1,but an excess of PEG/RPEG may be used, as it may be easily separatedfrom the polymer after completion of the reaction.

[0143] The values of f and h for the PEG blocks are determined by thePEG/RPEG chosen. Typically f and h are the same, when a single PEG/RPEGis used; but if two or more PEGs/RPEGs of different lengths are used,then mixtures of copolymers containing varying PEG block lengths can beobtained, and these mixtures may be separated if desired, by suchmolecular weight fractionation techniques as gel permeationchromatography. The value of g for the POE block is determined primarilyby the ratio of the di(ketene acetal) to the diol used to form the POE.

[0144] The triblock copolymers of formula Z are also formed in atwo-step synthesis.

[0145] In the first step, a PEG of the formula H-[OCH₂CH₂]h-OH isreacted with an excess of a di(ketene acetal) of formula III or formulaIV to form an intermediate of formula XI or formula XII:

[0146] In the second step, a diol of the formula HO—R¹—OH and a diol ofthe formula HO—R⁴—OH, and optionally a diol of the formulae HO—R²—OHand/or HO—R³—OH, or a mixture thereof, is reacted with the solution ofthe first step (containing the intermediate of formula XI or formula XIIand the excess di(ketene acetal)) to extend the POE blocks, therebyforming the triblock copolymer of formula Z.

[0147] Since the di(ketene acetal) and the diol react in a 1:1 ratio toform the POE blocks of the diblock copolymer, the quantities of the PEG,the di(ketene acetal), and the diol are chosen so that the molar amountof di(ketene acetal) is equal to the sum of the molar amounts of the PEGand the diol.

[0148] The value of h for the PEG block is determined by the PEG chosen.The values of g and j for the POE blocks are determined by the molarquantity of diol relative to the molar quantity of PEG: the greater themolar quantity of diol (assuming that the di(ketene acetal) is presentin at least an equimolar quantity), the longer are the POE blocks.Typically the POE blocks will be of equal lengths, on average.

[0149] In an alternative synthesis of the triblock copolymer of formulaZ, POE blocks terminated with di(ketene acetal) units (intermediates offormula 1× and formula X) are prepared, and reacted with 0.5 molarequivalent of PEG to terminate each end of the PEG with the POE blocks.

[0150] In any of the syntheses in which the copolymers may have anunreacted di(ketene acetal) terminal group, the copolymer may be reactedwith a hydroxy-containing compound, such as a C₁-C₄ alcohol, toterminate the copolymer with alkoxy units; and such alkoxy-terminatedcopolymers are included within the scope of the invention. Thehydroxy-containing compound, especially a C₁-C₄ alcohol, may be employedin excess and the unreacted excess easily separated during purificationof the polymer.

[0151] Suitable reaction conditions for the formation of the copolymersare those conditions well known for the formation of poly(ortho esters),such as are described in U.S. Pat. No. 5,968,543 and the other documentscited in the Background of the invention. Typically, the reaction takesplace in a polar aprotic solvent, especially tetrahydrofuran. A catalystmay be used if desired or necessary, and may be selected from thosecatalysts known to the art for the formation of orthoesters. Suitablesuch catalysts include iodine/pyridine, strong acids such asp-toluenesulfonic acid; Lewis acids, such as boron trichloride etherate,boron trifluoride etherate, tin oxychloride, phosphorus oxychloride,zinc chloride, phosphorus pentafluoride, antimony pentafluoride, stannicchloride, and the like; and Bronsted acids, such as polyphosphoric acid,polystyrenesulfonic acid, and the like. A particularly suitable catalystis p-toluenesulfonic acid. A typical amount of catalyst used is about0.2% by weight relative to the diketene acetal, though quantitiesbetween 0.005% and 2% may be used.

[0152] Suitable reaction temperatures are from room temperature to theboiling point of the solvent used, for example, between 20° C. and 70°C.; and suitable reaction times are between a few minutes and 48 hours,typically between 15 minutes and 24 hours.

[0153] Once the formation of the block copolymer is complete, thecopolymer can be isolated by precipitation in a non-polar aproticsolvent such as hexane. Typically, the reaction mixture containing thecopolymer (which may be cooled before the addition) is added slowly toabout ten volumes of the rapidly stirred solvent at room temperature.The precipitated block copolymer may be collected by filtration,decantation, or other suitable method, washed to remove unreactedmonomers or other contaminants, and dried, typically in a vacuum oven ata temperature below its melting point.

[0154] Uses of the Block Copolymers

[0155] While the block copolymers of this invention will find utility inany of the uses for which biodegradable polymers are useful, includingsuch uses as vehicles for the sustained release of active agents,orthopedic implants, degradable sutures, and the like, they will alsofind particular utility in applications where their nature as blockcopolymers having both hydrophobic and hydrophilic blocks confers aspecial benefit, and these uses will be addressed in greater detail,since a person of ordinary skill in the art will be well acquainted withthe uses of biodegradable polymers and will have no difficulty, havingregard to the skill of the art and this disclosure, in adapting theblock copolymers of this invention to such uses.

[0156] Micellar System for Targeting of Tissues with EPR (Tumors andInflamed Tissues)

[0157] Polymers useful as micellar delivery systems can be prepared byforming diblock, AB, or triblock, ABA or BAB, copolymers comprising ahydrophilic poly(ethylene glycol) A block and a hydrophobic poly(orthoester) B block.

[0158] When such block copolymers are placed in water, in which thepoly(ethylene glycol) block is soluble and the poly(ortho ester) blockis insoluble, the block copolymer chains will spontaneouslyself-aggregate to form micellar structures. The hydrodynamic diameter ofsuch micelles, which may be determined by methods such as dynamic lightscattering, will be in the order of 10-30 nm. As may be determined bymethods such as static light scattering, such micelles will containseveral hundred polymer chains. The micelles will undergo a secondary,reversible association, giving particles of an average diameter of about100 nm. While such micelles are too large to be excreted by the kidneys,individual block copolymers are not. Further, since the poly(orthoester) segments can be made to be biodegradable, facile renal excretionwill take place.

[0159] The major utility of such micellar systems resides in theirability to entrap and solubilize hydrophobic drugs in the hydrophobiccore. Such entrapment is easily carried out in a number of ways. Thus,the drug can be added to the aqueous solution containing micelles andincorporated by simple stirring, by heating to moderate temperatures, orby ultrasonication. The micelles are efficient carriers for a variety ofhydrophobic or insoluble active agents, and are particularly suitable ascarriers for anticancer agents, which will accumulate in the tumor by anendocytotic process.

[0160] Efficient entrapment of hydrophobic drugs requires a highlyhydrophobic core. Using AB, ABA, or BAB block copolymers where thehydrophobic B block forms a biodegradable, highly hydrophobic poly(orthoester) core will allow preparation of systems with significantlyenhanced entrapment efficiency relative to other biodegradable segmentssuch as poly(L-lactic-co-glycolic acid) copolymers.

[0161] While any of the anticancer agents that can form micellarcomplexes are suitable for this use, anticancer agents that areparticularly suitable for micellar tumor targeting are those with lowwater solubility or high aromatic content, such as the anthracyclineantibiotics (e.g. doxorubicin, daunorubicin, and epirubicin), mitomycinC, paclitaxel and its analogs (e.g. docetaxol), platinum analogs (e.g.cisplatin and carboplatin), and the like. Other agents may includeanticancer proteins, such as neocarzinostatin, L-asparaginase, and thelike, and photosensitizers used in photodynatic therapy. Similarly,while any of the anti-inflammatory agents that can form micellarcomplexes are suitable for this use, anti-inflammatory agents that areparticularly suitable for micellar targeting are those with low watersolubility or high aromatic content, such as the anti-inflammatorysteroids (e.g., cortisone, hydrocortisone, dexamethasone, prednisone,prednisolone, beclomethasone, betamethasone, flunisolide, fluocinoloneacetonide, fluocinonide, triamcinolone, and the like) and thenon-ionized NSAIDs (e.g., naproxen, nabumetone, ketoprofen, mefenamicacid, fenbufen, piroxicam, meloxicam, celecoxib, rofecoxib, and thelike).

[0162] Bioerodible Block Copolymer Matrix for Controlled Drug Delivery

[0163] In the block copolymers of this invention, phase separation willoccur where domains of the B block form within the continuous A-phase orvice versa. Such phase-separated material will have unique and usefulthermal properties. Specifically, unlike poly(ortho esters) containingshort segments of PEG within the poly(ortho ester), which when heatedwill gradually soften, PEG/POE AB, ABA, or BAB block copolymers haverelatively sharp melting points. Further, while poly(ortho esters)containing short segments of poly(ethylene glycol) that have lowsoftening temperatures have very poor mechanical properties, thecopolymers of this invention, even those having very low meltingtemperatures, will retain mechanical properties suitable for use asimplants.

[0164] The present block copolymers can be used for any use in whichbioerodible polymers are usable, such as vehicles for the sustainedrelease of an active agent.

[0165] To use the block copolymer as a sustained-release vehicle orcarrier, the active agent must be incorporated into a matrix of theblock copolymer or encapsulated within a capsule (or a “microcapsule” or“nanocapsule”, as those terms are sometimes used) of the blockcopolymer. Methods for the preparation of sustained-release dosage formsusing biodegradable polymers are well known in the art, as discussed inthe references cited in the “Description of the related art” section ofthis application, and in other references familiar to those of ordinaryskill in the art; so that a person of ordinary skill in the art wouldhave no difficulty, having regard to that skill and this disclosure, inpreparing sustained-release formulations using the block copolymer ofthis invention. Suitable active agents include therapeutic agents suchas pharmaceutical or pharmacological active agents, e.g. drugs andmedicaments, as well as prophylactic agents, diagnostic agents, andother chemicals or materials useful in preventing or treating disease.The compositions of this invention are particularly useful for thetherapeutic treatment of humans and other mammals, but may also be usedfor other animals. In addition, the sustained-release compositions ofthis invention may also be used for the release of cosmetic andagricultural agents, or for the release of biocides, such as fungicidesor other pesticides, into an environment where prolonged release of theactive agent is desired.

[0166] In the case of matrix formulations, the block copolymer is firstmixed with the active agent. High homogeneity may be achieved by mixingthe block copolymer in its heat softened state with the active agent,followed by lowering the temperature to harden the composition.Alternatively, the block copolymer can be dissolved in an appropriatecasting solvent, such as tetrahydrofuran, methylene chloride, chloroformor ethyl acetate, and the active agent can then be dispersed ordissolved in the block copolymer solution, followed by evaporating thesolvent to achieve the finished composition. Another method is grindinga solid block copolymer material into powder which is then mixed with apowdered active agent. The active agent may also be incorporated intothe mixture of monomers before polymerization provided that it is stableunder the polymerization conditions and does not interfere with thepolymerization reaction.

[0167] If the active agent is one that is unstable at elevatedtemperatures (e.g. above 40° C.), or in the presence of organic solventsor organic solvent/water mixtures, such as a protein, then specialpreparation techniques may be required to minimize the exposure of theactive agent to damaging conditions. Such techniques are disclosed in,for example, U.S. Pat. No. 5,620,697, which discloses ultrasonic meltingto form matrix-type pharmaceutical compositions, and 5,518,730, whichdiscloses melt-spinning, both of which techniques are designed tominimize the exposure of the polymer and active to elevatedtemperatures. Other methods are disclosed in the patents and literaturereferences cited elsewhere in this application.

[0168] An alternate method for the incorporation and release ofsensitive therapeutic agents is to use bioerodible poly(ortho esters)that have physical properties tailored for this incorporation. Forexample, the block copolymer may be chosen so that it is semi-solid andhas an ointment-like consistency, rather than being fully solid. Thus, ablock copolymer may be chosen that has a very high viscosity at normalbody temperature of 37° C. so that little if any deformation takes placeat that temperature. However, the viscosity of the block copolymer maydecrease substantially at temperatures no higher than 45° C., orpreferably by 40° C., so that injection of the material may be possibleat a temperature at which the active agent retains its activity.

[0169] The composition obtained from any of the above methods can bereadily processed into a variety of shapes and forms for implantation,insertion or placement on the body or into body cavities or passageways.For example, the block copolymer composition may be injection molded,extruded or compressed into a thin film or made into devices of variousgeometric shapes or forms such as flat, square, round, cylindrical,tubular, disc, ring and the like. Rod- or pellet-shaped devices may beimplanted through a trocar, such as is known for Norplant® implants, andthese or other shapes may be implanted by minor surgical procedures.Alternatively, a device may be implanted following a major surgicalprocedure such as tumor removal in the surgical treatment of cancer. Theimplantation of polymer wafers containing anticancer agents isdescribed, for example, in U.S. Pat. Nos. 5,626,862 and 5,651,986, andreferences cited therein; and the poly(ortho esters) of this inventionwill find utility in such applications.

[0170] The block copolymer composition may also be injected by syringesubcutaneously or intramuscularly as particles of 0.1 μm to 1000 μm,preferably 0.5 μm to 200 μm, and more preferably 1 μm to 150 μmsuspended in a pharmaceutically acceptable injection base. Liquidvehicles useful for suspending the drug-block copolymer composition forinjection include isotonic saline solution or oils (such as corn oil,cottonseed oil, peanut oil and sesame oil) which, if desired, maycontain other adjuvants.

[0171] Another injectable dosage form may be prepared from an activeagent mixed in a block copolymer of the present invention which has ansemi-solid consistency or which, when mixed with a suitable liquidexcipient, forms a semi-solid composition such as the compositionsdescribed in U.S. patent application Ser. No. 09/854,180 (InternationalPublication No. WO 01/85139). Such a dosage form may be administered byinjection. Such a dosage form may also be administered by directapplication to an area to be treated, such as by spreading into a woundwith a spatula.

[0172] The block copolymer composition administered by either injectionor implantation undergoes bioerosion in the body into non-toxic andnon-reactive materials. By controlling the number of hydrolysable bondsin the block copolymer, the active agent may be released at a desiredrate. Implants prepared from the present block copolymers in which theblock copolymer constitutes the matrix containing an active agent alsohave the advantage that they do not require removal because of thebioerodibility of the block copolymer.

[0173] In some cases, particles with cores of the pure active agentcoated with various thicknesses of the present block copolymer may bepreferred for sustained delivery of the active agent. Coating orencapsulation of discrete particles of the active agent may beaccomplished by conventional methods which are all well-known to theperson skilled in the art. For example, finely divided drug particlesmay be suspended in a solvent system (in which the drug is not soluble)containing the dissolved block copolymer and other excipients, followedby spray drying. Alternatively, the drug particles may be placed in arotating pan or a fluid-bed dryer and the block copolymer dissolved in acarrier solvent is sprayed onto the drug particles until a suitablecoating quantity is deposited on the particles to give a desiredthickness. The coating may also be achieved by suspending the drugparticles in a solvent system containing the dissolved block copolymerfollowed by adding to the suspension a non-solvent causing the blockcopolymer to precipitate and form a coating over the drug particles.

[0174] For the sustained release compositions, because the active agentwill be released over a controlled period of time, the agent usually ispresent in an amount which is greater than the conventional single dose.The relative proportions of the active agent and the block copolymer canvary over a wide range (e.g., 0.1-50 wt. %) depending on the therapeuticagent and the desired effect.

[0175] Sustained compositions of cosmetic and agricultural agents mayalso be prepared by any one of the methods as described above, using theblock copolymers of the present invention.

[0176] The solid block copolymers are also useful for a variety oforthopedic applications. For example, they can be used as fracturefixation devices for repair of osteochondral defects, ligament andtendon reconstructions and bone substitutes. In addition, the fact thatthe present block copolymers permit simultaneous selection of both adesired level of their mechano-physical state and a desired rate ofbioerodibility, also renders them attractive as grafts or scaffolds onwhich cells can be cultured in vitro prior to implantation to regeneratetissues. Tissues which can be regenerated using this approach includebut not limited to, bone, tendon, cartilage, ligaments, liver,intestine, ureter and skin tissues. For example, the block copolymersmay be used to regenerate skin for patients with burns or skin ulcers.Cartilages may be repaired by first isolating chondrocytes from apatient (or a donor), allowing them to proliferate on the scaffoldsprepared from the present block copolymers and re-implanting the cellsin the patient.

[0177] The block copolymer scaffolds or implants may further containother biologically active substances or synthetic inorganic materialssuch as reinforcing filler material for enhancing the mechanicalproperties of the scaffolds or implants (e.g. calcium sodiummetaphosphate fibers), antibiotics or bone growth factors to induceand/or promote orthopedic restoration and tissue regeneration.

[0178] The copolymer composition administered by either injection orimplantation undergoes bioerosion in the body into non-toxic andnon-reactive materials. By controlling the number of hydrolysable bondsin the polymer, the active agent may be released at a desired rate.Implants prepared from the present copolymers in which the copolymerconstitutes the matrix containing an active agent also have theadvantage that they do not require removal because of the bioerodibilityof the copolymer.

[0179] The compositions are also stable. The release rates of the activeagent are not affected by irradiation for sterilization.

[0180] Particular Compositions and Their Uses

[0181] Exemplary compositions of this invention, and their uses,include:

[0182] (1) compositions containing local anesthetics, optionally incombination with glucocorticosteroids such as dexamethasone, cortisone,hydrocortisone, prednisone, prednisolone, beclomethasone, betamethasone,flunisolide, fluocinolone acetonide, fluocinonide, triamcinolone, andthe like, for the prolonged relief of local pain or a prolonged nerveblockade;

[0183] (2) compositions containing cancer chemotherapeutic agents, suchas those listed above under “Active agents”, for deposition by syringeor by injection into tumors or operative sites from which a tumor hasbeen ablated, for tumor control or treatment and/or the suppression ofregrowth of the tumor from residual tumor cells after ablation of thetumor;

[0184] (3) compositions containing progestogens, such as flurogestone,medroxyprogesterone, norgestrel, norgestimate, norethindrone, and thelike, for estrus synchronization or contraception;

[0185] (4) compositions containing antimetabolites such as fluorouraciland the like, as an adjunct to glaucoma filtering surgery; compositionscontaining antiangiogenic agents such as combrestatin, contortrostatin,and anti-VEGF agents, for the treatment of macular degeneration andretinal angiogenesis; and other compositions for the controlled releaseof ophthalmic drugs to the eye;

[0186] (5) compositions containing therapeutic polypeptides (proteins),such as insulin, luteinizing hormone releasing factor antagonists, andthe like, for the controlled delivery of these polypeptides, avoidingthe need for daily or other frequent injection;

[0187] (6) compositions containing anti-inflammatory agents such as theNSAIDs, e.g., ibuprofen, naproxen, COX-1 or COX-2 inhibitors, and thelike, or anti-inflammatory steroids, for deposition by injection intoinflamed tissue or intra-articular injection;

[0188] (7) compositions containing antibiotics, for the prevention ortreatment of infection, especially for deposition into surgical sites tosuppress post-operative infection, or into or on wounds, for thesuppression of infection (e.g. from foreign bodies in the wound);

[0189] (8) compositions containing morphogenic proteins such as bonemorphogenic protein; and

[0190] (9) compositions containing DNA or other polynucleotides, such asantisense oligonucleotides.

[0191] Delivery of Controlled-Release Local Anesthetics by Injection

[0192] Local anesthetics induce a temporary nerve conduction block andprovide pain relief which lasts from a few minutes to a few hours. Theyare frequently used to prevent pain in surgical procedures, dentalmanipulations or injuries.

[0193] The synthetic local anesthetics may be divided into two groups:the slightly soluble compounds and the soluble compounds.Conventionally, the soluble local anesthetics can be applied topicallyand by injection, and the slightly soluble local anesthetics are usedonly for surface application. The local anesthetics conventionallyadministered by injection can also be divided into two groups, estersand non-esters. The esters include (1) benzoic acid esters (piperocaine,meprylcaine and isobucaine); (2) p-aminobenzoic acid esters (procaine,tetracaine, butethamine, propoxycaine, chloroprocaine); (3)m-aminobenzoic acid esters (metabutethamine, primacaine); and (4)p-ethoxybenzoic acid esters (parethoxycaine). The non-esters are largelyanilides (amides), and include bupivacaine, lidocaine, mepivacaine,pyrrocaine and prilocalne.

[0194] Many of the local anesthetics are conventionally used in the formof their acid addition salts, as this provides solubility in aqueousinjection media. However, because the presence of the large amount ofacid within such a local anesthetic acid addition salt will result inmore rapid degradation of the poly(ortho esters) or block copolymers ofthis invention and release of the local anesthetic, it is generallydesirable to use the local anesthetics in free base form, or with only asmall proportion of the acid addition salt present (addition of smallquantities of the acid addition salt may provide enhanced release ifdesired).

[0195] The semi-solid injectable form of a local anesthetic of thepresent invention is prepared by incorporating the local anesthetic intothe delivery vehicle in a manner as described above. The concentrationof the local anesthetic may vary from 1-60 wt. %, preferably 5-30 wt. %,e.g., about 10 wt. %. The semi-solid composition is then filled into asyringe with a 18-25 gauge needle, and injected into sites that arepainful or to be subjected to surgical procedures. The semi-solidinjectable composition of the present invention can be used forcontrolled delivery of both slightly soluble and soluble localanesthetics.

[0196] Because the duration of action of a local anesthetic isproportional to the time during which it is in actual contact withnervous tissues, the present injectable delivery system can maintainlocalization of the anesthetic at the nerve for an extended period oftime which will greatly prolong the effect of the anesthetic.

[0197] A number of authors, including in U.S. Pat. No. 6,046,187 andrelated patents, have suggested that the co-administration of aglucocorticosteroid may prolong or otherwise enhance the effect of localanesthetics, especially controlled-release local anesthetics; andformulations containing a local anesthetic and a glucocorticosteroid,and their uses for controlled release local anesthesia, are within thescope of this invention.

EXAMPLES

[0198] The following syntheses illustrate the preparation of blockcopolymers of this invention.

Example 1 Preparation of a Diblock Copolymer of Formula X

[0199] Under anhydrous conditions, 20 g (10 mmol) PEG 2000 mono-methylether (MPEG 2000) and 21.23 g (100 mmol) DETOSU are weighed into a 250mL flask and dissolved in 40 mL THF. A solution of p-toluenesulfonicacid in THF (0.05 mL, 20 mg/mL) is added to the MPEG 2000/DETOSUsolution to initiate the reaction between the MPEG 2000 and the DETOSU,and the reaction mixture is stirred for about 20 minutes. CDM (13.20 g,91.5 mmol), 0.375 g (2.5 mmol) MDEA, and 0.213 g (1 mmol) TEG-mGL in 40mL tetrahydrofuran are added to the flask, followed by another 0.05 mLof the p-toluenesulfonic acid solution. The reaction mixture is stirredfor about 30 minutes, and then added dropwise to about 1 L of hexanewith vigorous stirring, precipitating the diblock copolymer product,which is separated by filtration and dried in a vacuum oven.

Example 2 Preparation of a Triblock Copolymer of Formula Z

[0200] Under anhydrous conditions, 15 g (15 mmol) PEG 1000 and 21.23 g(100 mmol) DETOSU are weighed into a 250 mL flask and dissolved in 40 mLTHF. A solution of p-toluenesulfonic acid in THF (0.05 mL, 20 mg/mL) isadded to the PEG 1000/DETOSU solution to initiate the reaction betweenthe PEG 1000 and the DETOSU, and the reaction mixture is stirred forabout 20 minutes. CDM (11.52 g, 79.9 mmol), 0.750 g (5.0 mmol) MDEA, and0.226 g (0.85 nmmol) TEG-mGL in 40 mL tetrahydrofuran are added to theflask, followed by another 0.05 mL of the p-toluenesulfonic acidsolution. The reaction mixture is stirred for about 30 minutes, and thenadded dropwise to about 1 L of hexane with vigorous stirring,precipitating the triblock copolymer product, which is separated byfiltration and dried in a vacuum oven, giving a triblock POE-PEG-POEcopolymer.

[0201] Other Copolymers of Formula X, Y, and Z are Similarly Prepared

[0202] The foregoing is offered primarily for purposes of illustration.It will be readily apparent to those skilled in the art that themolecular structures, proportions of the reactant materials, methods ofuse and other parameters of the invention described herein may befurther modified or substituted in various ways without departing fromthe spirit and scope of the invention.

What is claimed is:
 1. A micellar pharmaceutical composition for thedelivery of a hydrophobic or water-insoluble active agent, comprisingthe active agent physically entrapped within but not covalently bondedto a drug carrier comprising a block copolymer of formula X, formula Y,or formula Z: R^(A)—[OCH₂CH₂]_(f)-[POE]_(g)-H  (X),R^(A)—[OCH₂CH₂]_(f)-[POE]_(g)-[OCH₂CH₂]_(h)—OR^(B)  (Y),H-A-[POE]_(g)-[OCH₂CH₂]_(h)-[POE]_(j)-H  (Z), where: R^(A) is C₁-C₄alkyl; R^(B) is C₁-C₄ alkyl; f and h are independently an integer from 2to 1000; g and j are independently an integer from 2 to 200; POE is apoly(ortho ester) unit of formula IA or formula IIA:

where R* is a C₁-C₄ alkyl; R is a bond, —(CH₂)—, or—(CH₂)_(b)—O—(CH₂)_(c)—; where a is an integer of 1 to 10, and b and care independently integers of 1 to 5; and each A is independentlyselected from R¹, R², R³, and R⁴, where R¹ is:

where: p is an integer of 1 to 20; R⁵ is hydrogen or C₁-C₄ alkyl; and R⁶is:

where: s is an integer of 0 to 30; t is an integer of 2 to 200; and R⁷is hydrogen or C₁-C₄ alkyl; R² is:

R³ is:

where: x is an integer of 0 to 30; y is an integer of 2 to 200; R⁸ ishydrogen or C₁-C₄ alkyl; R⁹ and R¹⁰ are independently C₁-C₁₂ alkylene;R¹¹ is hydrogen or C₁-C₆ alkyl and R¹² is C₁-C₆ alkyl; or R¹¹ and R¹²together are C₃-C₁₀ alkylene; and R⁴ is the residue of a diol containingat least one amine functionality incorporated therein; in which at least0.1 mol % of the A units are R¹, and at least 0.1 mol % of the A unitsare R⁴.
 2. The pharmaceutical composition of claim 1 where the fractionof the active agent is from 1% to 60% by weight of the composition. 3.The pharmaceutical composition of claim 2 where the fraction of theactive agent is from 5% to 30% by weight of the composition.
 4. Thepharmaceutical composition of claim 1 where the active agent is selectedfrom anti-infectives, antiseptics, steroids, therapeutic polypeptides,anti-inflammatory agents, cancer chemotherapeutic agents, narcotics,local anesthetics, antiangiogenic agents, vaccines, antigens, DNA, andantisense oligonucleotides.
 5. The pharmaceutical composition of claim 1where the active agent is a cancer chemotherapeutic agent.
 6. Thepharmaceutical composition of claim 1 where the active agent is ananti-inflammatory agent.
 7. A method of treating a disease statetreatable by controlled release local administration of an active agent,comprising locally administering a therapeutically effective amount ofthe active agent in the form of a pharmaceutical composition of claim 1.8. A composition for the sustained release of an active agent,comprising the active agent dispersed in a matrix comprising a blockcopolymer of formula X, formula Y, or formula Z:R^(A)—[OCH₂CH₂]_(f)-[POE]_(g)-H  (X),R^(A)—[OCH₂CH₂]_(f)-[POE]_(g)-[OCH₂CH₂]_(h)—OR^(B)  (Y),H-A-[POE]_(g)-[OCH₂CH₂]_(h)-[POE]_(j)-H  (Z), where: R^(A) is C₁-C₄alkyl; R^(B) is C₁-C₄ alkyl; f and h are independently an integer from 2to 1000; g and j are independently an integer from 2 to 200; POE is apoly(ortho ester) unit of formula IA or formula IIA:

where R* is a C₁-C₄ alkyl; R is a bond, —(CH₂)—, or—(CH₂)_(b)—O—(CH₂)_(c)—; where a is an integer of 1 to 10, and b and care independently integers of 1 to 5; and each A is independentlyselected from R¹, R², R³, and R⁴, where R¹ is:

where: p is an integer of 1 to 20; R⁵ is hydrogen or C₁-C₄ alkyl; and R⁶is:

where: s is an integer of 0 to 30; t is an integer of 2 to 200; and R⁷is hydrogen or C₁-C₄ alkyl; R² is:

R³ is:

where: x is an integer of 0 to 30; y is an integer of 2 to 200; R⁸ ishydrogen or C₁-C₄ alkyl; R⁹ and R¹⁰ are independently C₁-C₁₂ alkylene;R¹¹ is hydrogen or C₁-C₆ alkyl and R¹² is C₁-C₆ alkyl; or R¹¹ and R¹²together are C₃-C₁₀ alkylene; and R⁴ is the residue of a diol containingat least one amine functionality incorporated therein; in which at least0.1 mol % of the A units are R¹, and at least 0.1 mol % of the A unitsare R⁴.
 9. The pharmaceutical composition of claim 8 where the fractionof the active agent is from 1% to 60% by weight of the composition. 10.The pharmaceutical composition of claim 9 where the fraction of theactive agent is from 5% to 30% by weight of the composition.
 11. Thepharmaceutical composition of claim 8 where the active agent is selectedfrom anti-infectives, antiseptics, steroids, therapeutic polypeptides,anti-inflammatory agents, cancer chemotherapeutic agents, narcotics,local anesthetics, antiangiogenic agents, vaccines, antigens, DNA, andantisense oligonucleotides.
 12. The pharmaceutical composition of claim8 where the active agent is a local anesthetic.
 13. The pharmaceuticalcomposition of claim 12 further comprising a glucocorticosteroid.
 14. Amethod of treating a disease state treatable by controlled release localadministration of an active agent, comprising locally administering atherapeutically effective amount of the active agent in the form of apharmaceutical composition of claim
 8. 15. A method of preventing orrelieving local pain at a site in a mammal, comprising administering tothe site a therapeutically effective amount of a local anesthetic in theform of a pharmaceutically acceptable composition of claim
 12. 16. Adevice for orthopedic restoration or tissue regeneration comprising ablock copolymer of formula X, formula Y, or formula Z:R^(A)—[OCH₂CH₂]_(f)-[POE]_(g)-H  (X),R^(A)—[OCH₂CH₂]_(f)-[POE]_(g)-[OCH₂CH₂]_(h)—OR^(B)  (Y),H-A-[POE]_(g)-[OCH₂CH₂]_(h)-[POE]_(j)-H  (Z), where: R^(A) is C₁-C₄alkyl; R^(B) is C₁-C₄ alkyl; f and h are independently an integer from 2to 1000; g and j are independently an integer from 2 to 200; POE is apoly(ortho ester) unit of formula IA or formula IIA:

where R* is a C₁-C₄ alkyl; R is a bond, —(CH₂)—, or—(CH₂)_(b)—O—(CH₂)_(c)—; where a is an integer of 1 to 10, and b and care independently integers of 1 to 5; and each A is independentlyselected from R¹, R², R³, and R⁴, where R¹ is:

where: p is an integer of 1 to 20; R⁵ is hydrogen or C₁-C₄ alkyl; and R⁶is:

where: s is an integer of 0 to 30; t is an integer of 2 to 200; and R⁷is hydrogen or C₁-C₄ alkyl; R² is:

R³ is:

where: x is an integer of 0 to 30; y is an integer of 2 to 200; R⁸ ishydrogen or C₁-C₄ alkyl; R⁹ and R¹⁰ are independently C₁-C₁₂ alkylene;R¹¹ is hydrogen or C₁-C₆ alkyl and R¹² is C₁-C₆ alkyl; or R¹¹ and R¹²together are C₃-C₁₀ alkylene; and R⁴ is the residue of a diol containingat least one amine functionality incorporated therein; in which at least0.1 mol % of the A units are R¹, and at least 0.1 mol % of the A unitsare R⁴.